R. De Raedt

Cognitive control therapy and transcranial direct current stimulation for depression: A randomized, double-blinded, controlled trial

BACKGROUND Based on findings that major depressive disorder (MDD) is associated to decreased dorsolateral prefrontal cortical (DLPFC) activity; interventions that increase DLPFC activity might theoretically present antidepressant effects. Two of them are cognitive control therapy (CCT), a neurocognitive intervention that uses computer-based working memory exercises, and transcranial direct current stimulation (tDCS), which delivers weak, electric direct currents over the scalp. METHODS We investigated whether tDCS enhanced the effects of CCT in a double-blind trial, in which participants were randomized to sham tDCS and CCT (n=17) vs. active tDCS and CCT (n=20). CCT and tDCS were applied for 10 consecutive workdays. Clinicaltrials.gov identifier: NCT01434836. RESULTS Both CCT alone and combined with tDCS ameliorated depressive symptoms after the acute treatment period and at follow-up, with a response rate of approximately 25%. Older patients and those who presented better performance in the task throughout the trial (possibly indicating greater engagement and activation of the DLPFC) had greater depression improvement in the combined treatment group. LIMITATIONS Our exploratory findings should be further confirmed in prospective controlled trials. DISCUSSION CCT and tDCS combined might be beneficial for older depressed patients, particularly for those who have cognitive resources to adequately learn and improve task performance over time. This combined therapy might be specifically relevant in this subgroup that is more prone to present cognitive decline and prefrontal cortical atrophy.

Influence of high-frequency repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex on the inhibition of emotional information in healthy volunteers

BACKGROUND Evidence suggests that repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) might be a promising new treatment procedure for depression. However, underlying working mechanisms of this technique are yet unclear. Multiple sessions of rTMS may--apart from the reported antidepressant effects--cause primary improvements in attentional control over emotional information, modulated by changes in cortical brain excitability within stimulated prefrontal regions. METHOD In two experiments, we examined the temporary effects of high-frequency (HF) rTMS (10 Hz) applied over the left and right DLPFC on the attentional processing of emotional information and self-reported mood within samples of healthy volunteers. RESULTS The present study showed that one session of HF-rTMS over the right DLPFC produces instant impairments in the ability to inhibit negative information, in line with a characteristic cognitive vulnerability found in depressive pathology, whereas HF-rTMS of the left DLPFC did not lead to significant changes in attentional control. These effects could not be attributed to mood changes. CONCLUSIONS The findings of the present study may suggest a specific involvement of the right DLPFC in the attentional processing of emotional information.

Differentiation between mild cognitive impairment, Alzheimer's disease and depression by means of cued recall

BACKGROUND Discriminating Alzheimers disease (AD) and mild cognitive impairment (MCI) from depression is a challenge in psychogeriatric medicine. A study was set up to ascertain whether cued recall could be useful in differentiating early AD and MCI from depression among elderly individuals. METHOD The Visual Association Test (VAT) and the Memory Impairment Screen-plus (MIS-plus) were administered together with the Mini-Mental State Examination (MMSE) and the Geriatric Depression Scale (GDS) to 40 MCI patients, 35 mild AD patients, 46 depressed patients and 52 healthy control subjects. RESULTS A one-way analysis of variance (ANOVA) followed by post-hoc Scheffé tests showed that AD patients had significantly lower cued recall scores (i.e. combined VAT and MIS-plus scores) than MCI patients, who in turn had lower scores than depressed patients. The scores of depressed patients and controls were not significantly different. Discriminant analysis revealed that 94% of the AD patients and 96% of the depressed patients could be classified correctly by means of the GDS and the cued recall sores. Receiver operating characteristic (ROC) curves identified an optimal cut-off score of 8 (maximum score 12) for differentiating AD and MCI patients from depressed elderly patients and controls. Applying this cut-off, a sensitivity of 83% (58%) and a specificity of 85% (85%) was obtained when differentiating AD (MCI) from depression. CONCLUSIONS Cued recall, operationalized by the combined scores of VAT and MIS-plus, is a useful method for differentiating AD patients from depressed individuals and healthy controls. Probably because of the great heterogeneity among MCI patients, the diagnostic power of cued recall decreases when applied to differentiate MCI from depression.

Verbal cued recall as a predictor of conversion to Alzheimer's disease in Mild Cognitive Impairment.

This study was set up to investigate whether neuropsychological tests are able to predict conversion to AD among Mild Cognitive Impairment (MCI) patients.

Left and right High Frequency repetitive Transcranial Magnetic Stimulation of the dorsolateral prefrontal cortex does not affect mood in female volunteers

OBJECTIVE High Frequency repetitive Transcranial Magnetic Stimulation (HF-rTMS) has yielded divergent results concerning its effect on mood in normal volunteers. In a former study, we were unable to demonstrate negative mood effects after one session of HF-rTMS on the left dorsolateral prefrontal cortex (DLPFC) in a large group of healthy female volunteers: researchers had focused mainly on negative mood changes, overlooking a possible positive mood induction, while no studies had yet examined mood effects of HF-rTMS delivered on the right prefrontal cortex. In this study, we have tried to replicate our previous HF-rTMS findings on the left DLPFC in a new (large) group of healthy female subjects, and we focused especially on positive mood changes. We also extended our former research by stimulating the right DLPFC in a different but comparable (large) group of healthy female volunteers with the same HF-rTMS parameters. METHODS In this sham-controlled, single blind, crossover HF-rTMS study, stimulus parameters were an exact copy of our previous healthy volunteer study. To exclude individual anatomical differences, the left and right DLPFC were targeted under magnetic resonance (MRI) guidance. To examine subjective mood changes we used Visual Analogue Scales (VAS), the Profile of Mood States (POMS), and the Positive Affect and Negative Affect Schedule (PANAS), the latter to assure assessment of positive emotions. To detect any delayed mood changes, assessments were also re-administered 30min post-HF-rTMS. RESULTS We were unable to demonstrate immediate or delayed mood changes after one single active HF-rTMS session on the left or right DLPFC. CONCLUSIONS Although we took into account several methodological problems which might have confounded previous rTMS mood induction studies, the hypothesis that one single session of HF-rTMS on the left or on the right DLPFC can influence mood in healthy female volunteers was not supported. SIGNIFICANCE One HF-rTMS session has no effect on subjective mood in healthy female volunteers.

Mild cognitive impairment: what's in a name?

Background: Nowadays the term mild cognitive impairment (MCI) is used to fill the gap between cognitive changes associated with normal ageing and those associated with dementia. Despite some agreement in general definitions, MCI is still a heterogeneous clinical syndrome for which no DSM-IV criteria have yet been established. Criteria by Petersen et al. are presently the most applied in clinical practice. Moreover, little attention has been paid to the specific relation between MCI and depression. Objective: This review highlights some concerns about the concept of MCI and provides guidelines within the field of neuropsychology to solve them. In a second part, the paper focuses on the specific relationship between depression in the elderly and MCI. Results: We hypothesize that certain test instruments can be used to operationalize the criteria proposed by Petersen et al. Moreover, we suggest that cued recall might be of help to differentiate between progressive and non-progressive MCI. Concerning the specific relation between depression and MCI, we assume that elderly depression with concomitant cognitive problems can be seen as an MCI. Conclusion: The proposed adjustments and additions (neuropsychological instruments and the incorporation of depressive symptoms) in the diagnostic flowchart of Petersen may serve as useful tools for clinicians when making a diagnosis of MCI.

One left dorsolateral prefrontal cortical HF-rTMS session attenuates HPA-system sensitivity to critical feedback in healthy females

OBJECTIVE Although left dorsolateral prefrontal cortical (DLPFC) repetitive Transcranial Magnetic Stimulation (rTMS) is used to treat major depression, its underlying neurophysiological working mechanism remains to be determined. Prior research suggested that the clinical effects could be mediated by affecting the hypothalamic-pituitary-adrenal (HPA) system, but experimental studies in healthy individuals did not yield clear results. However, in healthy individuals, the influence of HF-rTMS on the HPA-system may only be detected when it is challenged. METHODS In 30 rTMS naïve healthy females we evaluated the effect of one sham-controlled high frequency (HF)-rTMS session applied to the left DLPFC on the stress hormone cortisol by collecting salivary cortisol samples. In order to increase stress levels, 5min after stimulation, all participants performed the Critical Feedback Task (CFT), during which they were criticized on their performance. To take possible mood influences into account, all participants were also assessed with Visual Analogue Scales (VAS). RESULTS The experimental procedure did not affect mood differently in the real or sham stimulation. Area under the curve (AUCi) analysis showed that one real HF-rTMS session significantly influenced HPA-system sensitivity, as demonstrated by a decrease in cortisol concentrations. The sham procedure yielded no effects. CONCLUSIONS In line with former observations in major depression, one real left DLPFC HF-rTMS session significantly influenced HPA-system sensitivity in experimentally stressed females, resulting in decreases in cortisol levels.

Reduced left subgenual anterior cingulate cortical activity during withdrawal-related emotions in melancholic depressed female patients

BACKGROUND Research regarding the neurocircuitry in mood disorders suggests an important role for affective information processing of the subgenual part of the anterior cingulate cortex (Cg25: Brodmann area 25). OBJECTIVE In this study, we focused on Cg25 neuronal responses in depressed females using a paradigm in which emotions are elicited without explicit cognitive control, relying on the salient nature of the mood inducing stimuli eliciting approach-related emotions (like happiness) or withdrawal-related emotions (like disgust). METHODS Twelve treatment-resistant melancholic depressed women and 12 healthy female control subjects were asked to passively view blocks of emotionally valenced baby faces while undergoing functional magnetic resonance imaging (fMRI). RESULTS Compared to the healthy females, the depressed patients displayed significantly higher bilateral Cg25 neuronal activities in both emotional conditions. In melancholically depressed women, we found significantly less left-sided than right-sided Cg25 neuronal activity during the withdrawal-related emotions, while right-sided Cg25 activity was comparable for both emotional responses. CONCLUSIONS Our results indicate that in depressed women the left Cg25 modulates intense visceral emotional responses to aversive visual stimuli. This could help explain why the left Cg25 provides a valid target region for antidepressant treatment strategies in unipolar melancholic depression.

The effect of one left-sided dorsolateral prefrontal sham-controlled HF-rTMS session on approach and withdrawal related emotional neuronal processes.

OBJECTIVE Although repetitive Transcranial Magnetic Stimulation (rTMS) is frequently used to examine emotional changes in healthy volunteers, it remains largely unknown how rTMS is able to influence emotion. METHODS In this sham-controlled, single-blind crossover study using fMRI, we examined in 20 right-handed healthy females whether a single high frequency (HF)-rTMS session applied to the left dorsolateral prefrontal cortex could influence emotional processing while focussing on blocks of positively and negatively valenced baby faces. RESULTS While positive information was being processed, we observed after one active HF-rTMS session enhanced neuronal activity in the left superior frontal cortex and right inferior parietal cortex. After sham HF-rTMS, we found significant decreases in neuronal activity in the left superior frontal cortex, the left inferior prefrontal cortex, as well as in the right posterior cingulate gyrus. When negative information was processed, one active stimulation attenuated neuronal activity in the right insula only. CONCLUSIONS Our findings suggest that during the processing of positive information one active session enhanced the ability to empathize with the depicted emotional stimuli, while during the processing of negative information it resulted in decreased psychophysiological reactions. SIGNIFICANCE These results provide new information on the working mechanism of left-sided HF-rTMS.

Impact of One HF-rTMS Session on Fine Motor Function in Right-Handed Healthy Female Subjects: A Comparison of Stimulation over the Left versus the Right Dorsolateral Prefrontal Cortex

Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool to investigate neural conduction in motor processes. Most rTMS research has been conducted by targeting the primary motor cortex. Several studies have also found increased psychomotor speed after rTMS of the dorsolateral prefrontal cortex (DLPFC). However, these studies were mainly performed in psychiatric patients, only targeting the left DLPFC, and often without sham control. Moreover, psychomotor speed is mostly measured based on tasks that also require higher executive functions. Methods: Here, we examined the lateralized effect of one sham-controlled high-frequency rTMS session applied to the left or right DLPFC on fine motor function in 36 healthy right-handed females, using the Fitts’ paradigm. Results: We found a significant improvement in psychomotor speed only after actively stimulating the right DLPFC. Conclusion: Our results support the assumption of a right prefrontal neural network implicated in visuomotor behavior and performance processes, and that the improvement in psychomotor speed is not a secondary effect of decreased mood.